This proposal describes a 5-year training program for the development of an independent academic career in Laboratory Medicine and Infectious Diseases. The program will promote the command of genomic and proteomic approaches applied to the study of viral pathogenesis. Kenneth L. Tyler will mentor the P.I.'s scientific development. Dr. Tyler is a recognized leader in the field of viral pathogenesis. As Professor of Neurology, Microbiology, Immunology, and Medicine, he has trained numerous postdoctoral fellows and graduate students. To enhance the training, the program will enlist the expertise of a multidisciplinary board of senior scientists, who will provide scientific and career advice. The University of Colorado provides an ideal setting for training physician-scientists by integrating expertise from diverse resources into customized programs. This environment maximizes the potential for the PI to establish a scientific niche from which a successful academic career can be constructed. Research will focus on delineating and targeting apoptotic signaling pathways in viral myocarditis. Dr.Tyler's laboratory has used reoviruses to study viral and cellular mechanisms of apoptotic cell death, both in vitro and in well-characterized murine models of viral encephalitis and myocarditis. Specific aims of this project are (1) to identify the importance of apoptosis as a critical determinant of virus-induced myocarditis, (2) to characterize virus-induced myocarditic signaling pathways in vitro and vivo at the transcriptional and translational levels, and (3) to target critical identified pathways in vivo, as a novel therapeutic strategy for viral myocarditis. Proposed experiments involve detailed analysis of infected murine cardiac myocytes and tissues, using myocarditic and non-myocarditic viruses. Virologic, histologic, immunohistochemical, genomic and proteomic approaches will be employed. Identified pathways will be targeted using specific inhibitors and mice with genetic mutations in pertinent signaling pathways. These studies are designed to identify specific cellular mechanisms of virus-induced apoptosis in the pathogenesis of viral myocarditis. Identification of these pathways is critical for the development of novel therapies for viral myocarditis and other diseases involving apoptotic tissue damage.